The present invention relates to a method for preventing or reducing the risk of or onset of cardiovascular events employing an HMG CoA reductase inhibitor, such as pravastatin.
Despite significant progress in reducing mortality due to atherosclerotic coronary artery disease (CAD) over the last several years, cardiovascular disease remains the major cause of death in most developed countries. The relation between CAD and elevated concentrations of serum total cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is well documented.
It is well established that lipid disorders are important factors in the development of coronary heart disease (CHD), Schettler, G., xe2x80x9cThe role of diet and drugs in lowering serum cholesterol in the postmyocardial infarction patient,xe2x80x9d Cardiovasc. Drugs Ther., 1989, 2/6 (795-799).
Glatter, T. R., xe2x80x9cHyperlipidemia. What is xe2x80x98normalxe2x80x99, who should be treated and how,xe2x80x9d Postgrad. Med., 1984, 76/6 (49-59), states that xe2x80x9cAs the Coronary Primary Prevention Trial has recently shown, a 1% reduction in cholesterol level produces a 2% reduction in risk of myocardial infarction.xe2x80x9d
Goldstein, J. L., et al, xe2x80x9cThe LDL receptor defect in familial hypercholesterolemia. Implications for pathogenesis and therapy,xe2x80x9d Med. Clin. North Am., 1982, 66/2 (335-362) indicate that xe2x80x9cfamilial hypercholesterolemia was the first genetic disorder recognized to cause myocardial infarction. To this day, it remains the outstanding example of a single gene mutation that causes both hypercholesterolemia and coronary atherosclerosis.xe2x80x9d
Satler, L. F., et al, xe2x80x9cReduction in coronary heart disease: Clinical and anatomical considerations,xe2x80x9d Clin. Cardiol., 1989, 12/8 (422-426) disclose that xe2x80x9cthe higher the total plasma cholesterol and low density lipoprotein cholesterol (LDL-C), the greater the risk that coronary artery disease will develop. Recently, clinical trials including the Coronary Drug Project, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), and the Helsinki Heart Study provided evidence that lowering cholesterol reduces the frequency of fatal and nonfatal coronary events.xe2x80x9d In addition, Satler et al disclose that other studies xe2x80x9cdemonstrated that lowering of cholesterol was associated with a decreased incidence of progression of coronary disease, as well as with the potential for reduction in the atherosclerotic plaque.xe2x80x9d
Wilhelmsen, L., xe2x80x9cPractical guidelines for drug therapy after myocardial infarction,xe2x80x9d Drugs, 1989, 38/6 (1000-1007) discloses that it is advisable to correct blood lipid disturbances in effective management of the postinfarction patient.
Yamamoto, A., et al, xe2x80x9cClinical features of familial hypercholesterolemia,xe2x80x9d Arteriosclerosis, January-February 1989, 9 (1 Suppl.) p I66-74, disclose that xe2x80x9cin addition to the low density lipoprotein (LDL) cholesterol level, higher triglyceride and lower high density lipoprotein (HDL) cholesterol levels correlate with an increased risk of ischemic heart disease.
Other references disclosing the relation between CAD and elevated concentrations of serum total cholesterol include
1. Canner P. L. et al, xe2x80x9cFifteen year mortality in Coronary Drug Project patients: long-term benefit with niacinxe2x80x9d, J. Am. Coll. Cardiol. 1986; 8:1245-1255.
2. Frick, M. H. et al, xe2x80x9cHelsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease,xe2x80x9d N. Engl. J. Med. 1987; 317:1237-1245.
3. Kannel, W. B. et al, xe2x80x9cSerum cholesterol, lipoproteins, and the risk of coronary heart disease: the Framingham Study,xe2x80x9d Ann. Intern. Med. 1971; 74:1-12.
4. xe2x80x9cThe Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease,xe2x80x9d JAMA 1984; 251-351-364.
5. Martin, M. J. et al, xe2x80x9cSerum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men,xe2x80x9d Lancet 1986; 2:933-936.
Efforts to further reduce the mortality rate from CAD should benefit from appropriate screening for, and treatment of, hypercholesterolemia. Primary hypercholesterolemia is initially treated with a low-cholesterol low-fat diet and lifestyle modification. If these measures are inadequate, lipid lowering drugs are then added. Agents currently available for the treatment of hypercholesterolemia include bile acid-binding resins, nicotinic acid, probucol, fibrates, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Pravastatin, a member of the latter class, in doses up to 40 mg/day, reduces serum LDL cholesterol an average of 32 to 34% and total cholesterol an average of 24 to 26% in patients with primary hypercholesterolemia. Hunninghake, D. B. et al, xe2x80x9cEfficacy and safety of pravastatin in patients with primary hypercholesterolemia, I: a dose-response study.xe2x80x9d Atherosclerosis 1990; 85:81-89.
In accordance with the present invention, surprisingly and unexpectedly, it has been found that patients with one or more risk factors for a coronary and/or cerebrovascular event such as hypercholesterolemia, who are treated an HMG CoA reductase inhibitor, such as pravastatin, experience a rapid marked and significant reduction in cardiovascular events. Thus, although a certain number of patients having one or more risk factors for coronary or cerebrovascular events are expected to suffer a cardiovascular incident, such as a myocardial infarction and/or unstable angina, it has unexpectedly been found that such patients when treated with an HMG CoA reductase inhibitor, such as pravastatin, have a rapid and sizable reduction in such cardiovascular events. What is even more remarkable is the fact that such reduction in cardiovascular events occur within one year and usually within 6 months of treatment and even sooner. This is especially significant inasmuch as until now it has been the generally held view that a treatment effect on cardiac event rates appears only after a lag phase of xe2x89xa72 years, as seen in the Coronary Primary Prevention Trial (JAMA 1984; 251:351-364) and the Helsinki Heart Study (N. Engl. J. Med. 1987; 317:1237-1245).
Thus, in accordance with the present invention, a method is provided for preventing onset of or reducing risk of a cardiovascular event in a patient having one or more risk factors for a coronary and/or cerebrovascular event wherein a therapeutically effective amount of an HMG CoA reductase inhibitor, preferably pravastatin, lovastatin, simvastatin and fluvastatin, more preferably pravastatin, is administered systemically, such as orally or parenterally.
The term xe2x80x9crisk factors for a coronary and/or cerebrovascular eventxe2x80x9d as employed herein refers to risk factors such as hypercholesterolemia, coronary artery disease (CAD), family history of coronary artery disease, hypertension, diabetes, cigarette smoking, cerebrovascular disease and/or male gender.
The term xe2x80x9ccoronary artery diseasexe2x80x9d (CAD) as employed herein refers to diseases including atherosclerosis of the coronary arteries, previous myocardial infarction, angina pectoris and/or heart failure.
The term xe2x80x9ccerebrovascular diseasexe2x80x9d as employed herein refers to diseases including atherosclerosis of the intracranial and/or extracranial arteries, stroke, and transient ischemic attacks.
The term xe2x80x9ccardiovascular event(s)xe2x80x9d or xe2x80x9cserious cardiovascular adverse event(s)xe2x80x9d as employed herein refers to coronary and/or cerebrovascular event(s) including primary myocardial infarction, secondary myocardial infarction, angina pectoris (including unstable angina), congestive heart failure, sudden cardiac death, cerebral infarction, syncope, transient ischemic attack and the like.
In accordance with the method of the invention, where the risk factor in patients to be treated is hypercholesterolemia, the serum total cholesterol concentrations will be at least 5.2 mmol/liter (at least 200 mg/dl). The patients may also have other risk factors for atherosclerotic coronary artery disease such as hypertension, previous myocardial infarction, smoker and the like.
Notwithstanding the above, it will be appreciated that in accordance with the present invention, the HMG CoA reductase inhibitor may be administered to patients irrespective of cholesterol levels and other risk factors to achieve the rapid reduction in cardiovascular events.
The HMG CoA reductase inhibitors suitable for use herein include, but are not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, velostatin (synvinolin or simvastatin) and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin, lovastatin or simvastatin being preferred. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, fluindostatin (Sandoz XU-62-320), pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)alkyll]pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle""s SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application Wo 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3-di-substituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydro-naphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, as well as other HMG CoA reductase inhibitors.
In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in U.S. Pat. No. 4,904,646, which compounds have the moiety 
wherein X is xe2x80x94Oxe2x80x94or xe2x80x94NHxe2x80x94, n is 1 or 2 and Z is a hydrophobic anchor.
Another class of HMG CoA reductase inhibitors suitable for use herein include phosphinic acid compounds disclosed in U.S. Pat. No. 5,091,378, which compounds have the moiety 
wherein X is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CH2Oxe2x80x94, where O is linked to Z, and Z is a hydrophobic anchor.
Most preferred is pravastatin.
The above-mentioned U.S. patents are incorporated herein by reference.
In carrying our the method of the present invention, the HMG CoA reductase inhibitor may be administered to mammalian species, such as dogs, cats, humans, etc., and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable. The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, anti-bacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like. Oral dosage forms are preferred, although parenteral forms are quite satisfactory as well.
The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
Thus, for oral administration, a satisfactory result may be obtained employing the HMG CoA reductase inhibitor in dosages employed, for example, for pravastatin, lovastatin and simvastatin as indicated in the Physician""s Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, per day in single or divided doses, and preferably from about 4 to about 200 mg per day in single or divided doses.
A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount of from about 0.5 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
Tablets of various sizes can be prepared, e.g., of about 1 to 2000 mg in total weight, containing the active substance in the ranges described above, with the remainder being a physiologically acceptable carrier or other materials according to accepted pharmaceutical practice. These tablets can, of course, be scored to provide for fractional doses. Gelatin capsules can be similarly formulated.
Liquid formulations can also be prepared by dissolving or suspending active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonsful.
Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, aspartame, lactose or saccharin; a flavoring agent such as orange, peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, water, alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.
Some of the active substances described above form commonly known, pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substances are therefore intended to include those common salts known to be substantially equivalent to the parent compound.
The formulations as described above will be administered for a prolonged period, that is, for as long as the potential for a cardiovascular event remains or the symptoms continue. Sustained release forms of such formulations which may provide such amounts biweekly, weekly, monthly and the like may also be employed. A dosing period of at least one to two weeks or until hypercholesterolemia and/or atherosclerosis has regressed are required to achieve minimal benefit.